Mitochondrial Diseases

If you talk to a General Practitioner about MELAS the chances are, they won't know what you mean. Of course they will be aware of genetic disorders and mitochondrial function but probably have little detail about specific disorders.

There is a fair amount of technical information available about mitochondrial disorders, and a few layman's explanations but not much to bridge the gap. Hopefully, this will be a not-to-technical but accurate description of a rare class of diseases.

You have probably heard of Chronic Fatigue Syndrome. This is one of the (many) symptoms of mitochondrial disorders. I suspect that some clinically diagnosed sufferers of CFS might have a mitochondrial disorder.

Mitochondrial disorders can be:

Somatic

Maternal hereditary

Somatic means that it is of the cells in the body which are not of sperm or egg. These diploid bodycells contain two chromosomes. Egg and sperm are haploid meaning only one chromosome). If a Mitochondrial disorder is Somatic, then it will not be passed down the line, and was not acquired from the mother. Somatic mitochondrial disorders may be acquired through:

exposure to toxins or effects of medicines.

as a consequence of old age

some diseases like hyperthyroidism, hypothyroidism, and hyperlipidemia may be a cause.

mtDNA

A lot of mtDNA is “coded” by nDNA

If the origin of a mitochondrial disease is hereditary, then it means that it can only be passed down from the mother. This is because the mitochondria is contained in the cell, but not in the nucleus, and the woman's un-fertilised egg is one big cell. This is the source of mitochondria.

There are no accepted criteria for diagnosis. The tests used to screen for mitochondrial diseases are often complicated to interpret. A diagnosis may require visual and biochemical examination of muscle tissue because a blood test is not likely to show any mutations. Red blood cells do not contain mitochondria. White blood cells contain mitochondria but since these are continually regenerated by the body, mutations are flushed out through natural selection.

There are no accepted guidelines to determine whether the diagnosis is correct. So it is not very likely that a diagnosis of “Definite” will be given. The reason for this is the symptoms of several treatable diseases and these combined disorders could “look like” a mitochondrial problem. Therefore it is important to test and diagnose each symptom thoroughly in case it is caused by something else that is treatable. As an example: a patient had myopathy and biopsy-proven ragged- red fiber disease and ALSO had intermittent bursts of thyroid hormone from a multinodular goiter.

It was not a mitochondrial disease. It seems weird, but the presentation of a new symptom proved that the patient may not have an incurable mitochondrial disease because the thyroid problem could make the same symptoms. This is why testing can (and should) take a long time.

Cell nucleus

Mitochondria contains separate DNA to the cell nucleus. It is thought that billions of years ago, mitochondria and cellular life happened onto a beneficial symbiosis. This means an arrangement where the survival one one depends on the other. Mitochondria need cells to reproduce and keep safe, and the cells need mitochondria because it takes part in a cellular energy cycle. This chemical cycle provides the power for the cell, and is involves with the expulsion of waste products.

Each mother's egg cell contains many mitochondria. Since the mitochondria exists between the cell wall and the nucleus, it is more vulnerable to mutation. There are several different kinds of mutations. One important thing to note is that there are many mitochondria in the egg cell. Only some might be damaged.

If (say) 1% are damaged, then the other 99% do just fine. Probably if 10% are damaged, then the other 90% do fine. But at some point there is a threshold where it becomes a problem. It's unlikely that a cell with 90% damaged mitochondria could be fertilised and grow into a viable foetus.

Each of the mother's cells will have a different mix of good to bad mitochondria. This means that some eggs will grow to full term and result in a healthy baby, and some will grow to full term and result in a baby who will later have problems producing energy properly and displacing waste properly.

All children of an affected mother, including males are likely to have some ratio of good to bad mitochondria. But males cannot pass on the disorder because all the sperms' energy needs are in the swimming tail. The tail drops off when the sperm enters the egg, and with it, go any bad mitochondria. In any case, the fastest most energetic sperms are likely to be the ones to get the prize.

When the mother's fertilised egg starts to divide, each division results in progressive specialisation. Some will develop into skin cells, some into heart muscle, some into brain tissue and so on. Since the original egg contained a ratio of good to bad mitochondria, some organs might be lucky to develop only with good mitochondria, while others might be unlucky and get, say more than 50% bad mitochondria. For those organs/special cells that get too many bad mitochondria, it is difficult to produce the required energy for the cell, and difficult for the waste products to be expelled.

Some kinds of cells in the body are regenerative like mucus and skin cells. The process of growing and shedding cells eventually flushes out the bad mitochondria. So the disease does not cause skin problems. But muscles need energy, and organs like the kidneys and heart and brain need a lot of energy. The cells in these types of organs are not highly regenerative, so if there is a deficient production of energy, those organs don't work so well, and if the cells can't get rid of waste products, then this causes problems too. Over time, depending on the ratio of bad to good mitochondria in each organ, the inability to expel waste products like lactic acid and the lack of energy can cause deterioration. If the brain is affected, then this can lead to a form of dementia. It can affect hearing, the optic nerve, and other nerves in the body because they too need a lot of energy.

Diagnosis is very difficult. There are a lot of disorders and diseases that have symptoms like a mitochondrial problem and the tests that are done are difficult to interpret. Also, because the disease can affect different people and different cells in different ways, and produce different symptoms, it's not easy to make a diagnosis based only on symptoms. Red blood cells do not contain mitochondria, so it's not possible for siblings and parents and children to be screened with a simple blood test. In any case, blood cells are regenerative. A test would have to target a very specific mutation and since there are so many possible mutations, and each test is expensive, blood testing is not a useful primary tool for diagnosis.

Treatment

There is no cure, but there are possible treatments and so accurate diagnosis is essential. Although it is usually thought to be a progressive disease, the rate of progression varies hugely between cases, so some might progress relatively rapidly, and other very slowly. Some symptoms might be so slight that a diagnosis is never sought, and some might be debilitating. Some people have been known to improve spontaneously. So there is always hope.

None, one or more of the following can be affected with low, medium or high symptoms:

Early symptoms are often mis-diagnosed as far as cause and effect is concerned. Even something like anorexia could be “the eating disorder” or caused by a mitochondrial disease where the ability to process food is impaired. Other minor symptoms that could be independent diseases or related symptoms include things like:

vascular disease

chronic fatigue syndrome (CFS)

fibromyalgia

psychosomatic illness

cramps (large and small muscles)

Weakness – sometimes progresses from mild in the morning to more later in the day.

Droopy eyelids, double vision, difficulty maintaining steady gaze

facial paralysis

It's important to realise that just because someone has a symptom like one of the ones above, it does not directly or automatically mean the cause is a mitochondrial disease. It's much more likely to be something else. After all, almost everyone gets cramp at some time or another.

The problems that an affected person experiences throughout life is linked to the concentration of defective mitochondria that is distributed at birth. Those with high concentrations in one or more organs or cell groups will experience symptoms earlier – perhaps in childhood, and from then on carrying the burden over a longer period of time as more issues arise. Those that only have a small concentration of defective mitochondria are not likely to ever see any symptoms. Obviously there is a graduating scale between no effect and serious effects.

There are several “phenotypes” of mitochondria disease. The word “phenotype” is used instead of saying “classifications of observable symptoms” or something like that. Each phenotype is noted with a name and certain characteristics. One phenotype is MELAS, and another is MERRF, there are some more types too:

Phenotypes

These are the phenotypes, and some key features. There mitochondrial DNA can mutate in several different ways, and some of these ways result in certain characteristics. You can see there is some overlap from one to the other, so it's not easy to pick one particular label.

Altered state of mind. An impaired understanding of reality. Any of: delusions, hallucinations, confusion, disorganised speech, exaggerated or diminished emotions, or bizarre behaviour. Social withdrawal and inability to take care of work, relationships, or even basic personal care. The individual generally has no awareness of his or her abnormality. (Atypical psychosis)

Nerves - possible symptoms

muscle weakness,

pain

temperature instability,

inappropriate sweating (or lack of sweating) which can cause heat stroke at normal

temperatures.

dizzy spells

bladder dysfunction.

Affected nerves that control automatic (unconscious) movement can contribute to gastrointestinal “blockages”.

Loss of deep tendon reflexes and weakness

Heart

In some patients, cardiac disease is the first sign of mitochondrial cytopathy.

All patients with mitochondrial cell disorders should undergo electrocardiography regularly. A pacemaker or other intervention should be considered before symptoms arise if the electrocardiographic findings worsen.

Liver

Uncontrolled blood sugar levels. (This can cause a lot of complications) Usually first seen in childhood. Do not fast (cease eating) for long periods to avoid complications.

This and other kidney related symptoms are usually not seen in adults.

Loss of amino acids and electrolytes in the urine, especially in affected infants.

The kidneys may fail to excrete acids into the urine, which causes a person’s blood to remain too acidic. Without proper treatment, chronic acidity of the blood leads to growth retardation, kidney stones, bone disease, chronic kidney disease, and possibly total kidney failure.

Pancreas

Diabetes is a common late feature of mitochondrial diseases often associated with the MELAS mutation.

Fatigue

Only a small fraction of those with chronic fatigue syndrome have a mitochondrial cytopathy. This means that people who present with CFC are not routinely screened for a mitochondria disorder. But those who's medical tests are exhaustive and inconclusive, should possibly be screened for a mitochondrial disorder.

TESTS

Ragged red fibres.

The ragged fibres are not found on every muscle-fibre in a biopsy. There will be a percentage. If it is more than 2%, then this is considered a significant symptom. On its own, it does not necessarily mean MELAS for example.

Ragged blue fibres.

This can indicate clumps of mutant mtDNA. Another test is to compare the level of mutant mitochondrial DNA in cells from different parts of the body. If there is a significant ratio of mutant mtDNA in two or more types – like 20% to 30% this is a significant indicator.

An electric test.

The energy cycle in a cell involves the movement of electrons in and out of the cell. There is a test (called a polarographic assessment) using cells taken from the body and then even cultured in a dish. It essentially measures something to do with electrical conductivity. Mutant cells inhibit the movement of electrons so with this test, it's possible to compare results between two separate sources and known normal results.

If a specific mutation is suspected, then it's worth testing the blood – specifically the white blood cells. The tests look for specific point mutations in the mtDNA. Most laboratories only test for somewhere between 3 and 15 mutation types. A related test is called “southern blot” which looks for big missing chunks of DNA or large duplicated chunks. It is possible (but expensive) to screen the entire mtDNA in the white blood cells.

Retinitis pigmentosa ( Damage to the retina )

Optic atrophy (damaged optic nerve → dim vision, reduced field of vision.) LHON often presents with these symptoms and sometimes might be the only symptoms.

Of the phenotypes earlier described, some are known to be caused by specific mutations. So it's pointless to test a mutation for a phenotype that has no symptom. An example is “If there is no optic atrophy (problem with the optic nerve), then there is no point testing for LHON).

Possible treatments:

There is no cure, but things called “cofactors” might help in some cases.

Coenzyme Q10 might help reduce lactic acid and improve muscle strength. No significant side effects. Levocarnitine might in some improve strength, reverse cardiomyopathy, improve gastrointestinal movements but is (as of 2001) not proven for mitochondrial disorders. Side effects could be intestinal cramps.

B – vitamins might be beneficial as a trial after consultation with a specialist.

Antioxidants make theoretical sense as a treatment because they sweep up DNA-damaging 'free radicals'.

Avoid stress. IMPORTANT !

Avoid fasting

Avoid toxins

Benefits of Treatment and Effectiveness of Therapies Vary

treatment may be beneficial and noted immediately in some disorders

benefit of treatment may take a few months to notice

benefit of treatment may never be noticed, but the treatment may be effective in delaying or stopping the progression of the disease

some patients may not benefit from therapy

Disclaimer

As always - seek proper medical advise if you are worried about symptoms. Knowledge is a powerful tool but like any tool, it can be used positively or negatively. I wrote this for information purposes and you should not draw conclusions or take actions without qualified medical supervision. Mitochondrial diseases are extremely difficult to diagnose because the symptoms they produce vary widely among identical causes, and also mimic many mainstream treatable diseases. Probably the most significant symptom on top of several of the others listed in this article would be a long-term intolerance to exercise, starting in childhood.

Comments

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Manna in the wild 6 years agofrom Australia

We are symbiotic! Take a away our resident bacteria, and prehistoric DNA, and we would die. It's quite amazing isn't it?

Kelly Umphenour 6 years agofrom St. Louis, MO

Very interesting Manna....I actually loved Biology in college...this was like a great refresher course:). I had no idea that Fibromyalgia was related to the mitochondria at all...or that there was even such a classification of diseases. I knew only females have this tyoe of DNA and that it is really a reliable source of DNA for testing if you have a female subject. I didn't know much else though - awesome.

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